Receptors are those entities on or in a cell which recognize and bind drugs, hormones or other specific substances. After binding with the receptor, these substances may act to initiate or block biochemical and physiological sequences. Such initiation or blockage is often referred to as transduction. Thus, the receptor binding properties of a particular compound dictate the physiological effects that a particular compound will produce.
Opiate receptors are responsible for mediating analgesia. There are several known opiate receptor types, among the known opiate receptor subtypes are the mu, delta and kappa receptors. All three of these receptor subtypes are known to mediate analgesia, but each differs considerably in their other pharmacological effects. For instance, mu receptors additionally mediate respiratory depression and inhibit gastrointestinal transit.
Compounds structurally capable of binding at receptor sites may induce a variety of biological effects, all of which are useful in attaining a variety of pharmacological and therapeutic effects. For example, antagonists bind to the receptor but do not transduce the biological system to produce a response. Thus, antagonists can block the action of naturally occurring hormones and have great therapeutic value.
Somatostatin is a cyclic tetradecapeptide which is known to interact with numerous receptor systems, including the opiate receptors. Natural occurring somatostatin has the formula: ##STR2##
Peptides, such as somatostatin, are identified by amino acid sequence using established abbreviations. For example, as used herein, "Ala" stands for Alanine, "Gly" stands for Glycine, "Cys" stands for Cysteine, "Lys" stands for Lysine, "Asn" stands for Asparagine, "Phe" stands for Phenylalanine, "Trp" stands for Tryptophan, "Thr" stands for Threonine, "Arg" stands for Arginine and "Pen" stands for Penicillamine. Polypeptide derivatives in which one or more of the amino acids have been replaced by another amino acid are often described by reference to the basic compound and the position and the nature of the substitution. The position of substitution is usually identified by reference to the number of the amino acid in the sequence starting with the amino acid at the amino terminus of the peptide chain. For example, the somatostatin analog, ##STR3## is written as ##STR4## signifying the 5-12 amino acid residues of naturally occurring somatostatin. Additionally, amino acids may exist as stereoisomers in both L and D configurations.
Somatostatin is believed to exert a variety of hormonal actions such as inhibition of growth hormone release from the pituitary gland, inhibition of insulin release in the pancreas, inhibition of glucagon release in the pancreas, and interact with opiate receptors. Additionally, it has been reported that ##STR5## acts as a mu opioid antagonist. See Maurer, R., Gaehwiler, B. H., Buescher, H. H., Hill, R. C. and Roemer, D., Proc. Natl. Acad. Sci. USA 79, 4815-4817 (1982), which is herein specifically incorporated by reference.